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Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia

Riccardo Ballarò, Patrizia Lopalco, Valentina Audrito, Marc Beltrà, Fabrizio Pin, Roberto Angelini Orcid Logo, Paola Costelli, Angela Corcelli, Andrea Bonetto, Hazel H Szeto, Thomas M O'Connell, Fabio Penna

Cancers, Volume: 13, Issue: 4

Swansea University Author: Roberto Angelini Orcid Logo

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DOI (Published version): 10.3390/cancers13040850

Abstract

Cachexia is a complex metabolic syndrome frequently occurring in cancer patients and exacerbated by chemotherapy. In skeletal muscle of cancer hosts, reduced oxidative capacity and low intracellular ATP resulting from abnormal mitochondrial function were described. : The present study aimed at evalu...

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Published in: Cancers
ISSN: 2072-6694
Published: 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa57169
first_indexed 2021-06-18T14:03:18Z
last_indexed 2021-08-12T03:14:34Z
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In skeletal muscle of cancer hosts, reduced oxidative capacity and low intracellular ATP resulting from abnormal mitochondrial function were described. : The present study aimed at evaluating the ability of the mitochondria-targeted compound SS-31 to counteract muscle wasting and altered metabolism in C26-bearing (C26) mice either receiving chemotherapy (OXFU: oxaliplatin plus 5-fluorouracil) or not. : Mitochondrial dysfunction in C26-bearing (C26) mice associated with alterations of cardiolipin fatty acid chains. Selectively targeting cardiolipin with SS-31 partially counteracted body wasting and prevented the reduction of glycolytic myofiber area. SS-31 prompted muscle mitochondrial succinate dehydrogenase (SDH) activity and rescued intracellular ATP levels, although it was unable to counteract mitochondrial protein loss. Progressively increased dosing of SS-31 to C26 OXFU mice showed transient (21 days) beneficial effects on body and muscle weight loss before the onset of a refractory end-stage condition (28 days). At day 21, SS-31 prevented mitochondrial loss and abnormal autophagy/mitophagy. Skeletal muscle, liver and plasma metabolomes were analyzed, showing marked energy and protein metabolism alterations in tumor hosts. SS-31 partially modulated skeletal muscle and liver metabolome, likely reflecting an improved systemic energy homeostasis. : The results suggest that targeting mitochondrial function may be as important as targeting protein anabolism/catabolism for the prevention of cancer cachexia. 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spelling 2021-08-11T15:12:27.4426714 v2 57169 2021-06-18 Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia 6405b7880498750d41c93c6ff89cff96 0000-0001-5136-5921 Roberto Angelini Roberto Angelini true false 2021-06-18 MEDS Cachexia is a complex metabolic syndrome frequently occurring in cancer patients and exacerbated by chemotherapy. In skeletal muscle of cancer hosts, reduced oxidative capacity and low intracellular ATP resulting from abnormal mitochondrial function were described. : The present study aimed at evaluating the ability of the mitochondria-targeted compound SS-31 to counteract muscle wasting and altered metabolism in C26-bearing (C26) mice either receiving chemotherapy (OXFU: oxaliplatin plus 5-fluorouracil) or not. : Mitochondrial dysfunction in C26-bearing (C26) mice associated with alterations of cardiolipin fatty acid chains. Selectively targeting cardiolipin with SS-31 partially counteracted body wasting and prevented the reduction of glycolytic myofiber area. SS-31 prompted muscle mitochondrial succinate dehydrogenase (SDH) activity and rescued intracellular ATP levels, although it was unable to counteract mitochondrial protein loss. Progressively increased dosing of SS-31 to C26 OXFU mice showed transient (21 days) beneficial effects on body and muscle weight loss before the onset of a refractory end-stage condition (28 days). At day 21, SS-31 prevented mitochondrial loss and abnormal autophagy/mitophagy. Skeletal muscle, liver and plasma metabolomes were analyzed, showing marked energy and protein metabolism alterations in tumor hosts. SS-31 partially modulated skeletal muscle and liver metabolome, likely reflecting an improved systemic energy homeostasis. : The results suggest that targeting mitochondrial function may be as important as targeting protein anabolism/catabolism for the prevention of cancer cachexia. With this in mind, prospective multi-modal therapies including SS-31 are warranted. Journal Article Cancers 13 4 2072-6694 SS-31, cancer cachexia, liver, metabolomics, mitochondria, muscle wasting 18 2 2021 2021-02-18 10.3390/cancers13040850 Special Issue Cancer-Associated Cachexia COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Università degli Studi di Torino Grant: Ex-60% funds V Foundation for Cancer Research Grant: V2017-021 American Cancer Society Grant: 132013-RSG-18-010-01-CCG Associazione Italiana per la Ricerca sul Cancro Grant: IG 2018-ID. 21963 project 2021-08-11T15:12:27.4426714 2021-06-18T14:53:58.8357891 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Riccardo Ballarò 1 Patrizia Lopalco 2 Valentina Audrito 3 Marc Beltrà 4 Fabrizio Pin 5 Roberto Angelini 0000-0001-5136-5921 6 Paola Costelli 7 Angela Corcelli 8 Andrea Bonetto 9 Hazel H Szeto 10 Thomas M O'Connell 11 Fabio Penna 12 57169__20194__6d4dee19be5c4453ae701f5e80fe6e13.pdf 57169.VOR.pdf 2021-06-18T15:01:40.7587882 Output 3769370 application/pdf Version of Record true Copyright: © 2021 by the authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license true eng https://creativecommons.org/licenses/by/4.0/
title Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia
spellingShingle Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia
Roberto Angelini
title_short Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia
title_full Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia
title_fullStr Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia
title_full_unstemmed Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia
title_sort Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia
author_id_str_mv 6405b7880498750d41c93c6ff89cff96
author_id_fullname_str_mv 6405b7880498750d41c93c6ff89cff96_***_Roberto Angelini
author Roberto Angelini
author2 Riccardo Ballarò
Patrizia Lopalco
Valentina Audrito
Marc Beltrà
Fabrizio Pin
Roberto Angelini
Paola Costelli
Angela Corcelli
Andrea Bonetto
Hazel H Szeto
Thomas M O'Connell
Fabio Penna
format Journal article
container_title Cancers
container_volume 13
container_issue 4
publishDate 2021
institution Swansea University
issn 2072-6694
doi_str_mv 10.3390/cancers13040850
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description Cachexia is a complex metabolic syndrome frequently occurring in cancer patients and exacerbated by chemotherapy. In skeletal muscle of cancer hosts, reduced oxidative capacity and low intracellular ATP resulting from abnormal mitochondrial function were described. : The present study aimed at evaluating the ability of the mitochondria-targeted compound SS-31 to counteract muscle wasting and altered metabolism in C26-bearing (C26) mice either receiving chemotherapy (OXFU: oxaliplatin plus 5-fluorouracil) or not. : Mitochondrial dysfunction in C26-bearing (C26) mice associated with alterations of cardiolipin fatty acid chains. Selectively targeting cardiolipin with SS-31 partially counteracted body wasting and prevented the reduction of glycolytic myofiber area. SS-31 prompted muscle mitochondrial succinate dehydrogenase (SDH) activity and rescued intracellular ATP levels, although it was unable to counteract mitochondrial protein loss. Progressively increased dosing of SS-31 to C26 OXFU mice showed transient (21 days) beneficial effects on body and muscle weight loss before the onset of a refractory end-stage condition (28 days). At day 21, SS-31 prevented mitochondrial loss and abnormal autophagy/mitophagy. Skeletal muscle, liver and plasma metabolomes were analyzed, showing marked energy and protein metabolism alterations in tumor hosts. SS-31 partially modulated skeletal muscle and liver metabolome, likely reflecting an improved systemic energy homeostasis. : The results suggest that targeting mitochondrial function may be as important as targeting protein anabolism/catabolism for the prevention of cancer cachexia. With this in mind, prospective multi-modal therapies including SS-31 are warranted.
published_date 2021-02-18T20:14:50Z
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